This 15-year prospective cohort study of 950 patients shows that, although cryoglobulinemic syndrome (CS) has no influence on the overall survival of chronic hepatitis C virus (HCV)-infected patients, it does modify the natural history of the disease. Patients who were CS-positive were more likely to develop renal insufficiency, neurologic impairment, and B-cell non-Hodgkin lymphoma (NHL). Patients who did not have mixed cryoglobulinemia (MC) or CS at all were more likely to develop liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).

However, in spite of different morbidity features and causes of death, the 15-year survival rate, which was the primary endpoint of this study, was similar in the CS vs. MC-negative groups (70.2% vs. 71.7%).

This study assessed a cohort of 950 chronically HCV-infected patients every three months, from 1990 to 2010, the only long-term analysis of cryogenic vasculitis in HCV. As such, it is able to distinguish outcomes such as fibrosis and cirrhosis more accurately than previous studies.

According to the previous literature, small amounts of cryoglobins can be detected in about 40% of HCV patients, and 12-15% develop full-blown CS. CS symptoms include cutaneous vasculitis, fatigue, arthralgia, membranoproliferative glomerulonephritis, and peripheral neuropathy. A meta-analysis found a significant association between cryoglobulinemia and cirrhosis. However, the association between cryoglobulinemia and liver fibrosis has been inconsistent.

The present study refined these associations (see table below).

CS- positive

MC- negative

Enrolled

184

704

Completed study

141

601

15-year survival

70.2%

71.7%

Liver fibrosis

53%

85%

Cirrhosis

14.2%

24.9%

Hepatocellular carcinoma

7.5%

20.3%

Renal insufficiency

32.6%

3%

Neurologic impairment

31.2%

4.8%

B-cell non-Hodgkin lymphoma

15%

7.1%

Some differences between CS and MC-negative patients were:

• Purpura. Among the CS patients, 90% had palpable purpura; none of the MC-negative patients did. At the time of study admission, only 6 (4.2%) of the CS patients had chronic leg ulcers, but by followup, 41 patients (29%) developed nonhealing cutaneous ulcers requiring multiple hospital admissions. • Weakness and arthralgia. The CS patients were more likely to have weakness (86.5% vs. 47%, p<.0001), and arthralgia or nonerosive arthritis (63.1% vs. 16%, p<.0001). • Immunology. CS patients had higher levels of γ-globulin, IgG, IgM, and rheumatoid factor. MC-negative patients had higher levels of C4. • Liver fibrosis. The estimated progression rate to liver fibrosis was lower in CS-positive than in MC-negative patients (53% vs. 85%, p < 0.05). This suggests that cryoglobulins have only a slight impact on liver fibrosis, and will not be useful as a prognostic indicator for cirrhosis. • Cirrhosis and hepatocellular carcinoma (HCC). The 15-year cumulative probabilities of developing cirrhosis and HCC were both lower for CS than for MC-negative patients (14.2% vs. 24.9%, p < 0.005 and 7.5% vs. 20.3%, p = 0.003, respectively). • Renal insufficiency and neurologic impairment were significantly more frequent in CS than in MC-negative patients (32.6% vs. 3%, p < 0.0001 and 31.2% vs. 4.8%, p < 0.0001, respectively). • B-cell non-Hodgkin lymphoma (NHL). The risk of developing B-cell NHL was significantly higher in CS than MC-negative patients (15% vs. 7.1%, p = 0.003). This is because MC develops from HCV-driven B-cell deregulation.

Cryoglobins never cleared spontaneously. Among the 141 CS patients, there was a “remarkable prevalence” of type II MC, in 125 patients (88.6%), with type III in 16 patients (11.4%). Two patients switched from Type II to type III cryoglobulinemia, perhaps through loss of the B-cell clonotype. This switch was accompanied by loss of vasculitis, normalization of C4, and lowering of rheumatoid factor activity. This suggests that damage is related to monoclonal IgM-rheumatoid factor molecules, which can activate the complement cascade.

During the 15 years, 212 patients died (28.6%). The overall mortality rate (28.3%) was identical in the two groups. The cause of death was liver-related in 33% of the CS and 52.9% of the MC-negative group. Death from renal failure (33% vs. 4.3%) and septic shock (14.3% vs. 4.3%) were more common in the CS than MC-negative group. Cardiac and respiratory mortality were similar.

About half the patients were treated with antiviral therapy. Survival was significantly better in patients who chose therapy. Antiviral therapy consisted of interferon-α or pegylated interferon-α monotherapy, and interferon-α or pegylated interferon-α plus ribavirin.

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